2.an insight into the regulatory mechanisms of cells by dr ibrahi m

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  • Renovation (also called remodeling) is the process of improving a structure. 
  • Cytokines (Greek cyto-, cell; and -kinos, movement) are a diverse group of soluble proteins, peptides, or glycoproteins which act as hormonal regulators or signaling molecules at nano- to- picomolar concentrations and help in cell signaling. The term "cytokine" encompasses a large and diverse family of regulators produced throughout the body by cells of diverse embryological origin.
  • Osteoclasts are differentiated from hemopoietic cells
  • A modern working definition of a gene is "a locatable region of genomic sequence, corresponding to a unit of inheritance, which is associated with regulatory regions, transcribed regions, and or other functional sequence regions .
  • Osteoprotegerin (OPG), also known as osteoclastogenesis inhibitory factor (OCIF), or tumor necrosis factor receptor superfamily member 11B (TNFRSF11B), is a protein that in humans is encoded by the TNFRSF11B gene.[1]Osteoprotegerin is a cytokine receptor, and a member of the tumor necrosis factor (TNF) receptor superfamily.
  • Tartarate resistant acid phosphatase (TRAP) is an active enzyme, which plays a role in bone resorption inside andoutside the osteoclast cell.
  • Such structures keep the dentin protected against the immunologic system during the development of the natural tolerance, and in case the dentinary proteins are exposed, they may cause an immunologic response against the “self” components of the organism, known as an autoimmune reaction.Once exposed to the immunologic system, a cascade of events takes place for the lymphocytes to recognize and activate other cell types to differentiate in order to eliminate the “nonself” components.
  • 2.an insight into the regulatory mechanisms of cells by dr ibrahi m

    1. 1. An insight into the regulatory mechanisms of cells involved in resorption of dental hard tissues JOMFP 2013 :17 (2); 228-232 Mamata Kamat, Rudrayya Puranik, Shrinivas Vanaki, Sharad Kamat DR IBRAHIM
    2. 2. CONTENTS • • • • INTRODUCTION KEY CELLS IN RESORPTION REGULATION OF RESORPTION CONCLUSION
    3. 3. INTRODUCTION • The skeleton is a metabolically active organ system, comprising of • tissue-specific cells and • extracellular matrix (ECM) • that undergoes continuous remodeling throughout life.
    4. 4. BONE RESORPTION • Complex process involving highly coordinated interactions between osteoblasts and osteoclasts. • MODULATED BY:• Receptor activator of nuclear factor-κB (RANK) • Receptor activator of nuclear factor-κB ligand (RANKL) • Osteoprotegerin (OPG)
    5. 5. KEY CELLS IN RESORPTIONMonocytes and macrophages IRRITATION Release Of many proinflammatory cytokines MONOCYTES Differentiate MACROPHAGES
    6. 6. CLASTIC CELLS • Osteoclast • Odontoclast • Dentinoclast • Cementoclast
    7. 7. Osteoclasts Osteoclasts are tissue-specific bone-resorbing multinucleated giant cells, characterized by specialized membrane structure, clear zone, and ruffled borders
    8. 8. REGULATION OF RESORPTION • Bone resorption involves highly coordinated interaction between osteoblasts and osteoclasts that are modulated by enzymes, hormones,and RANK/RANKL/OPG system.
    9. 9. OPG • Mature protein of 380 amino acids. • Lacks transmembrane and cytoplasmic domains and is secreted as a soluble protein. • Osteoclast formation and activation is critically regulated by the RANKL/RANK/OPG. • The major biological action of OPG is inhibition of osteoclast differentiation,resorptive function and stimulation of osteoclast apoptosis. • Clinical use of OPG as an anti-resorptive agent for treating a variety of bone disorders characterized by increased osteoclast activity.
    10. 10. RANK • 616-amino acid peptide on the cell surface of osteoclast precursors. • Transforming growth factor-β (TGF-β) and vitamin D3 (D3), increases RANK mRNA. • Dexamethasone also enhances the mRNA expression of RANK.
    11. 11. RANKL • 317-amino acid peptide produced by osteoblastic lineage cells and activated T cells. • When RANKL is expressed by cells of osteoblastic lineage, it is cell-bound and when expressed by T-lymphocytes it is known as soluble (s-RANKL). • The role of RANKL, together with another very important protein ligand, macrophage colony stimulating factor (M-CSF) which binds to its receptor c-forms, is to promote osteoclast formation, fusion, differentiation, activation, an d survival, thus favouring bone resorption. • The biological effects of RANKL are produced when it binds to RANK.
    12. 12. • Bone, bone marrow and lymphoid tissue including fetal liver, lymph nodes, spleen and thymus express high levels of mRNA for RANKL. • Lower levels can be detected in heart, lung, thyroid, and placenta. • The soluble form of RANKL with M-CSF(macrophage colony stimulating factor) induces osteoclast formation even in the absence of cellular presentation.
    13. 13. • RANKL is produced by activated T cells as a soluble protein, and therefore bone resorption is regulated by the immune system, where T-cell expression of RANKL may contribute to pathological conditions such as periodontitis and autoimmune arthritis.
    14. 14. RESORPTION physiological Tooth eruption And shedding. pathological
    15. 15. • OPG is expressed by odontoblasts, ameloblasts, and dental pulp cells. • whereas RANK by odontoclasts, or by mononucleated precursors. • RANKL is expressed by odontoblasts, pulp, periodontal ligament (PDL) fibroblasts, and cementoblasts. • As in osteoclasts, RANKL is also expressed in odontoclasts, suggesting an autocrine or paracrine effect of this regulator on these cells.
    16. 16. • The resorbing activity of odontoclasts is related to the expression of the OPG/RANKL/RANK system by PDL cells. • It has been shown that PDL cells, isolated from either non-resorbing deciduous teeth or permanent teeth, express OPG, but not RANKL. • In contrast, PDL cells derived from resorbing deciduous teeth predominantly express RANKL and less OPG. • RANKL regulates odontoclast differentiation and dose-dependently increases odontoclast resorbing activity. • OPG suppresses the RANKL-induced activation of resorbing activity in odontoclasts.
    17. 17. • During permanent tooth eruption, cytotrophic factors released from the dental follicle and/or the stellate reticulum, such as parathyroid hormone-related peptide (PTHrP), interleukin-1α, and TGF-β1, stimulate the expression of RANKL. • Out of these factors, PTHrP controls the regulation of relative expression levels of RANKL/OPG on dental follicle cells, as well as in human PDL cells. • PTHrP increases RANKL and down regulates OPG expression via a cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) -independent pathway, consequently leading to physiological root resorption of deciduous teeth and successful eruption of permanent teeth..
    18. 18. • The differentiation and activation of localized preodontoclasts is also influenced by M-CSF. It is expressed by odontoblasts, ameloblasts, and dental pulp cells and its mechanism of action appears to involve upregulation of RANK and downregulation of OPG gene expression. • Recent studies have suggested that the cells of dental pulp may have some cytokine-producing cells, which mediate monocyte-macrophage lineage to form osteoclasts/odontoclasts
    19. 19. • T-cells can be activated to express RANKL, thereby inducing differentiation and activation of preodontoclast cells under the influence of locally produced cytokines. • The odontoblasts and fibroblasts, which express RANKL, interact with mononuclear progenitors and produce active odontoclasts. • Cytokines, IL-β, prostaglandin E2, TNF-α, or hormones such as dexamethasone and 1, 25 dihydroxycolecalciferol (OH) 2 D3, induced by the weakened PDL, stimulate expression of RANKL by PDL fibroblasts, leading to the recruitment of active odontoclasts and thus begin the resorption process. • Recent studies, have corroborated that cementoblasts also express RANKL and OPG, which is modulated by PTHrP. • Cementoblasts secrete large quantities of OPG under non-resorbing conditions, which could be the reason why cementum is more protected than bone from resorption.
    20. 20. • Tartarate resistant acid phosphatase (TRAP) can remove phosphate groups from osteopontin, an event that subsequently disrupts adhesion of osteoclasts to the bone. • Intracellularly TRAP has been localized in the transcytotic vesicles of osteoclasts(vesicles fuse with transcytotic vesicles transporting matrix degradation products).
    21. 21. • Root resorption is related to mechanical factors and biological activity. • During the dentinogenesis, the coronal dentin is protected by the recently formed enamel, stellate reticulum, stratum intermedium, and by the ameloblasts. • The root dentin is protected by Hertwig’s epithelial root sheath, cementum, and after the fragmentation of the sheath, by the cementoblasts and cementum. • In the case of dentin, osteoclasts are the primary cells involved in root resorption.
    22. 22. CONCLUSION • Knowledge on the mechanisms involved in physiologic root resorption process may enable us to delay or even inhibit exfoliation of primary teeth in those cases where the permanent teeth are not present. • Development of therapeutic drugs.

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